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Defective Mitochondrial Cardiolipin Remodeling Dampens HIF-1? Expression in Hypoxia.

ABSTRACT: Mitochondria fulfill vital metabolic functions and act as crucial cellular signaling hubs, integrating their metabolic status into the cellular context. Here, we show that defective cardiolipin remodeling, upon loss of the cardiolipin acyl transferase tafazzin, decreases HIF-1? signaling in hypoxia. Tafazzin deficiency does not affect posttranslational HIF-1? regulation but rather HIF-1? gene expression, a dysfunction recapitulated in iPSC-derived cardiomyocytes from Barth syndrome patients with tafazzin deficiency. RNA-seq analyses confirmed drastically altered signaling in tafazzin mutant cells. In hypoxia, tafazzin-deficient cells display reduced production of reactive oxygen species (ROS) perturbing NF-?B activation and concomitantly HIF-1? gene expression. Tafazzin-deficient mice hearts display reduced HIF-1? levels and undergo maladaptive hypertrophy with heart failure in response to pressure overload challenge. We conclude that defective mitochondrial cardiolipin remodeling dampens HIF-1? signaling due to a lack of NF-?B activation through reduced mitochondrial ROS production, decreasing HIF-1? transcription.

SUBMITTER: Chowdhury A

PROVIDER: S-EPMC6205837 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Defective Mitochondrial Cardiolipin Remodeling Dampens HIF-1α Expression in Hypoxia.

Chowdhury Arpita A Aich Abhishek A Jain Gaurav G Wozny Katharina K Lüchtenborg Christian C Hartmann Magnus M Bernhard Olaf O Balleiniger Martina M Alfar Ezzaldin Ahmed EA Zieseniss Anke A Toischer Karl K Guan Kaomei K Rizzoli Silvio O SO Brügger Britta B Fischer Andrè A Katschinski Dörthe M DM Rehling Peter P Dudek Jan J

Cell reports 20181001 3

Mitochondria fulfill vital metabolic functions and act as crucial cellular signaling hubs, integrating their metabolic status into the cellular context. Here, we show that defective cardiolipin remodeling, upon loss of the cardiolipin acyl transferase tafazzin, decreases HIF-1α signaling in hypoxia. Tafazzin deficiency does not affect posttranslational HIF-1α regulation but rather HIF-1α gene expression, a dysfunction recapitulated in iPSC-derived cardiomyocytes from Barth syndrome patients with ...[more]

PMID: 30332638

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Project description:IntroductionHypoxia is an important characteristic of gastric mucosal diseases, and hypoxia-inducible factor-1α (HIF-1α) contributes to microenvironment disturbance and metabolic spectrum abnormalities. However, the underlying mechanism of HIF-1α and its association with mitochondrial dysfunction in gastric mucosal lesions under hypoxia have not been fully clarified.ObjectivesTo evaluate the effects of hypoxia-induced HIF-1α on the development of gastric mucosal lesions.MethodsPortal hypertensive gastropathy (PHG) and gastric cancer (GC) were selected as representative diseases of benign and malignant gastric lesions, respectively. Gastric tissues from patients diagnosed with the above diseases were collected. Portal hypertension (PHT)-induced mouse models in METTL3 mutant or NLRP3-deficient littermates were established, and nude mouse gastric graft tumour models with relevant inhibitors were generated. The mechanisms underlying hypoxic condition, mitochondrial dysfunction and metabolic alterations in gastric mucosal lesions were further analysed.ResultsHIF-1α, which can mediate mitochondrial dysfunction via upregulation of METTL3/IGF2BP3-dependent dynamin-related protein 1 (Drp1) N6-methyladenosine modification to increase mitochondrial reactive oxygen species (mtROS) production, was elevated under hypoxic conditions in human and mouse portal hypertensive gastric mucosa and GC tissues. While blocking HIF-1α with PX-478, inhibiting Drp1-dependent mitochondrial fission via mitochondrial division inhibitor 1 (Mdivi-1) treatment or METTL3 mutation alleviated this process. Furthermore, HIF-1α influenced energy metabolism by enhancing glycolysis via lactate dehydrogenase A. In addition, HIF-1α-induced Drp1-dependent mitochondrial fission also enhanced glycolysis. Drp1-dependent mitochondrial fission and enhanced glycolysis were associated with alterations in antioxidant enzyme activity and dysfunction of the mitochondrial electron transport chain, resulting in massive mtROS production, which was needed for activation of NLRP3 inflammasome to aggravate the development of the PHG and GC.ConclusionsUnder hypoxic conditions, HIF-1α enhances mitochondrial dysfunction via Drp1-dependent mitochondrial fission and influences the metabolic profile by altering glycolysis to increase mtROS production, which can trigger NLRP3 inflammasome activation and mucosal microenvironment alterations to contribute to the development of benign and malignant gastric mucosal lesions.

Dataset Information

Defective Mitochondrial Cardiolipin Remodeling Dampens HIF-1? Expression in Hypoxia.

Publications

Defective Mitochondrial Cardiolipin Remodeling Dampens HIF-1α Expression in Hypoxia.

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